The insulin-like growth factor-I receptor (IGF-IR) activation mediates cell proliferation and prevents apoptosis. It also has other important cellular effects, mediated by downstream signaling pathways. A. IGF-1R activation stimulates cell cycle progression and plays a role in DNA repair. IGF-1R activation stimulates the expression of 14-3-3 sigma a protein previously considered to regulate cell cycle G2/M arrest. MCF-7 cells were studied and the level of 14-3-3 sigma was reduced using siRNA which led to a delay in S phase of the cell cycle in IGF-1-treated cells, suggesting that 14-3-3 sigma is a mediator of the IGF-1-induced cell cycle proliferation. B. Using microarray technology we have demonstrated that IGF-IR activation in NIH-3T3 fibroblast, specifically increases gene expression of a number of genes. Two of these genes, Twist and TDAG51, were not previously known to be influenced by IGF-I. Furthermore our studies using antisense and siRNA technologies demonstrated that reduced levels of these two proteins led to a reduction in IGF-I-induced anti-apoptosis, suggesting that not only are they expressed by IGF-I but they are important in the IGF-I signaling pathways. Future studies will determine the signaling cascades involved in these processes.